Clinically relevant copy number variants (CNVs) accounted for 4% of positive molecular diagnoses in 2342 patients tested for inherited cardiomyopathies and channelopathies.
Does an integrated screening strategy encompassing SNVs, indels, and CNVs improve diagnostic yield in patients with diagnosed or suspected cardiomyopathies or channelopathies?
The systematic inclusion of copy number variants (CNVs) in targeted NGS panels enhances the diagnostic yield for inherited cardiac diseases, accounting for 4% of positive genetic diagnoses.
Abstract Background Inherited cardiac diseases, such as cardiomyopathies and channelopathies, are among the leading causes of sudden cardiac death. Genetic testing plays a key role in their diagnosis and risk stratification. Traditionally, efforts in cardiogenetics have focused on detecting single nucleotide variants (SNVs) and small insertions/deletions (indels). However, this approach may overlook other relevant genomic alterations. Copy number variants (CNVs), now systematically assessed across all genes included in targeted panels, represent an additional and important source of pathogenic variation. Purpose This study aims to assess the impact of an integrated screening strategy that encompasses SNVs, indels, and CNVs on overall diagnostic yield in inherited cardiomyopathies and channelopathies. Methods Between November 2022 and July 2025, 2342 index cases with diagnosed or suspected cardiomyopathies or channelopathies referred to our laboratory for genetic testing were analysed. Variants were identified through targeted Next-Generation Sequencing (NGS) multigene panel. CNVs were detected using a read-depth approach and subsequently confirmed by orthogonal molecular techniques, including Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Diagnostic outcomes were classified in accordance with international guidelines. Results A molecular genetic diagnosis was established in 16% of patients (n = 388). Among these, 16 clinically relevant CNVs (likely pathogenic or pathogenic) were identified, representing 4% of positive findings. The distribution of CNVs varied across phenotypes, underscoring their heterogeneous contribution to different disease subtypes. Conclusions Clinically relevant CNVs represent a non-negligible proportion of molecular diagnoses in cardiogenetics. Their systematic inclusion alongside SNV and indel analysis enhances overall diagnostic yield and supports more comprehensive patient care. These findings align with recent evidence on the role of CNVs in inherited cardiovascular disorders. Advances in NGS-based CNVs detection now enable reliable integration of this methodology into routine diagnostic pipelines, although challenges in clinical interpretation sometimes remain.
Pinho et al. (2026) studied this question. Clinically relevant copy number variants (CNVs) accounted for 4% of positive molecular diagnoses in 2342 patients tested for inherited cardiomyopathies and channelopathies.